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WO2017025493A1 - Inhibiteurs quinoléine d'ezh2 - Google Patents

Inhibiteurs quinoléine d'ezh2 Download PDF

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Publication number
WO2017025493A1
WO2017025493A1 PCT/EP2016/068844 EP2016068844W WO2017025493A1 WO 2017025493 A1 WO2017025493 A1 WO 2017025493A1 EP 2016068844 W EP2016068844 W EP 2016068844W WO 2017025493 A1 WO2017025493 A1 WO 2017025493A1
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Prior art keywords
alkyl
group
methyl
phenyl
alkoxy
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PCT/EP2016/068844
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Inventor
Amaury Ernesto FERNANDEZ-MONTALVAN
Carlo STRESEMANN
Clara CHRIST
Detlef STÖCKIGT
Ulrike RÖHN
Antonius Ter Laak
Stefan Prechtl
Stefanie BUNSE
Timo Stellfeld
Ingo Hartung
Andrew J. Phillips
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Bayer Pharma AG
Broad Institute Inc
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Bayer Pharma AG
Broad Institute Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to quinolines, to a method for their preparation, to intermediates for their preparation, to pharmaceutical compositions, and to the use thereof.
  • Epigenetic changes refer to modifications in gene expression without alterations of the DNA sequence.
  • the DNA within eukaryotic cell nuclei is packaged together with histones and other proteins to form the complex known as chromatin.
  • Gene transcription is regulated by selective, enzyme-catalyzed post-translational modifications of the histone proteins (Jenuwein and Allis, Science, 2001, 10;293(5532): 1074-80).
  • the transcription of each gene can change from high-level expression to complete silencing, depending on the influence of the histone modification pattern which regulates the accessibility of promoters and the activity of the transcription machinery (Li et al, Cell, 2007, 23;128(4):707-19).
  • the Polycomb Repressive Complex 2 (PRC2) has emerged as a key histone modifying complex frequently de-regulated in cancer (Deb et al, Mol Cancer Res., 2014, 12(5):639-53).
  • PRC2 has a histone methyltransferase function responsible for the mono-, di- and tri-methylation of lysine-27 of histone H3 (H3K27).
  • Methylation of H3K27 is a repressive chromatin mark correlated with silencing of gene expression.
  • PRC2 is composed of the catalytic SET domain-containing histone methyltransferase EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1 (enhancer of zeste homolog 1) and core accessory proteins EED, SUZ12, and RbAp48.
  • EZH2 histone methyltransferase
  • EZH1 enhancer of zeste homolog 1
  • core accessory proteins EED, SUZ12, and RbAp48 core accessory proteins
  • the PRC2 complex is a master regulator that controls differentiation by repression of lineage control genes (Bracken and Helin, Nat Rev Cancer., 2009, 9(l l):773-84).
  • Overexpression of core proteins of PRC2 has been found in a wide variety of cancers (Simon and Lange, Mutat Res., 2008, l ;647(l-2):21-9).
  • PRC2 was proposed as a therapeutic target since it was demonstrated that different alterations ⁇ e.g., somatic copy number aberrations in KDM6A, mutations of the methyltransferase MLL2, increased EZH2 expression, and increased H3K27me3) converged to transcriptional profiles leading to silencing of PRC2-target genes (Dubuc et al, Acta Neuropathol., 2013, 125(3):373-84; Robinson et al, Nature, 2012, 2;488(7409):43-8; Alimova et al, hit J Cancer, 2012, 15;131(8): 1800-9).
  • H3K27 methylation caused silencing of key tumor suppressor genes such as pl5/16, DAB2IP and CDH1 (Gil and Peters, Nat Rev Mol Cell Biol., 2006,7(9) :667-77; Min et al.
  • PRC2 was validated as an important oncogenic driver in experiments where overexpression of EZH2 induced neoplastic transformation of benign epithelial cells, and this activity was dependent on the catalytic SET domain (Kleer et al, Proc Natl Acad Sci USA., 2003, 30;100(20): 11606-11). Knockdown of EZH2 has been demonstrated to cause re-expression of tumor suppressor genes, as well as inhibition of proliferation, invasion and migration (Crea et al. Cancer Metastasis Rev., 2012, 31(3- 4):753-61).
  • WO 2013/120104 and WO 2014/151142 disclose carboxamide derivatives as inhibitors of EZH2.
  • WO 2012/118812 discloses substituted 6,5-fused bicyclic heteroaryl compounds as - -
  • indole, indazole or azaindole derivatives as inhibitors of EZH2 are disclosed.
  • WO 2013/049770 discloses a method of treating cancer, inter alia comprising the administration of an EZH2 inhibitor.
  • WO 2013/067296, WO 2013/067300 and WO 2013/076302 disclose methods of treating T-cell mediated immune diseases or T-cell mediated hypersensitivity diseases which comprise administering to a human in need thereof an effective amount of a compound which inhibits EZH2 and/or EZH1.
  • WO 2014/097041 discloses aryl and heteroaryl fused lactams and WO 2015/104677 and WO 2015/110999 disclose heterocyclic compounds as inhibitors of EZH2.
  • the present invention relates to compounds of general formula (I)
  • R represents a group selected from Ci-C6-alkyl-, C 2 -C6-alkenyl-, C3-C7-cycloalkyl-, (C3-C7- cycloalkyl)-(L 1 )-, 4- to 7-membered monocyclic heterocycloalkyl-, 4- to 7-membered monocyclic heterocycloalkyl-(L 1 )-, Ci-C6-haloalkyl-, C 2 -C6-haloalkenyl-, Ci-C6-alkoxy-, Ci-Ce-haloalkoxy-, (Ci-C 3 -alkoxy)-(Ci-C 3 -alkyl)-, -NR 6 R 7 and phenyl-(Ci-C 3 -alkyl)-, wherein any C3-C7-cycloalkyl- or 4- to 7-membered monocyclic heterocycloalkyl- group is optionally substituted with one, two, or
  • two R 11 groups together if attached to adjacent ring atoms of a phenyl- or 5- to 6-membered monocyclic heteroaryl- group, represent a group selected from -CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -0-, -O-CH2-O-, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -0- and -0-CH 2 -CH 2 -0-;
  • L 1 represents a group selected from -CH 2 -, -CH 2 -O- and -0-;
  • L 3 represents, independently for each occurrence, a group selected from -CH 2 - and -CH 2 CH 2 -; and to N-oxides, salts, tautomers, or stereoisomers of said compounds, and to salts of said N- oxides, tautomers, or stereoisomers.
  • the present invention relates to compounds of general formula (I) - -
  • R represents a group selected from Ci-C6-alkyl-, Ci-C6-haloalkyl-, Ci-C6-alkoxy-,
  • R 2 represents a Ci-C3-alkyl- group;
  • R 3 represents a Ci-C3-alkyl- group
  • R 4 represents a Ci-C3-alkyl- group
  • R 5 represents hydrogen, hydroxy-, halogen-, -NR 6 R 7 , or a group selected from aryl-, heteroaryl-, heterocycloalkyl-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 8 ;
  • R 6 and R 7 represent, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a
  • R 8 represents a group selected from halogen-, Ci-C6-alkyl-, (Ci-C6-alkyl)-OH, -NR 6 R 7 ,
  • the present invention relates to compounds of general formula (I).
  • R 1 represents a group selected from Ci-C t-alkyl-, Ci-C t-haloaikyl-, and Ci-C t-alkoxy-;
  • R 2 represents a Ci-C3-alkyl- group;
  • R 3 represents a Ci-C3-alkyl- group;
  • R 4 represents a Ci-C3-alkyl- group;
  • R 5 represents hydrogen, hydroxy, halogen-, -NR 6 R 7 , or a group selected from phenyl-, heteroaryl-, and heterocycloalkyl-, wherein phenyl-, heteroaryl-, and heterocycloalkyl- are optionally substituted with one, two or three substituents, each substituent independently selected from R 8 ;
  • R 6 and R 7 represent, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 6-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with
  • R 8 represents halogen, Ci-C 4 -alkyl-, -(Ci-C 4 -alkyl)-OH, -NR 6 R 7 , -(Ci-C 4 -alkyl)-NR 6 R 7 ,
  • the present invention relates to compounds of general formula (I)
  • R 1 represents a group selected from -0-CH(CH 3 ) 2 , -0-(CH 3 )-(CH 2 CH 3 ), -(CH 2 ) 2 CH 3 ,
  • R 2 represents methyl
  • R 3 represents methyl
  • R 4 represents methyl
  • R 5 represents a group selected from hydrogen, hydroxy-, and chlorine, or a group selected from phenyl-, pyridine-3-yl-, pyridine-4-yl-, pyrimidine-5-yl-, oxazole-4-yl-, and piperazine-l-yl, said group being optionally substituted with one, two or three substituents, each substituent independently selected from methyl, chlorine, -N-(CH 3 ) 2 , -(CH 2 )-N-(CH 3 )2, -0-(CH 2 ) 3 -N-(CH 3 )2, - CH(CH 3 ) 2 OH, -N-morpholinyl, -(CH 2 )-N-morpholinyl, -(CO)-N-morpholinyl, and -N-piperazin-l - yl, wherein -N-piperazin-l -yl is optionally subtituted by methyl; or a salt, tautomer
  • the present invention relates to compounds of general formula (I) in which
  • R 1 represents Ci-C t-alkyl- or Ci-C t-alkoxy-
  • R 2 represents a Ci-C 3 -alkyl- group
  • R 3 represents a Ci-C 3 -alkyl- group
  • R 4 represents a Ci-C 3 -alkyl- group
  • R 5 represents heteroaryl-, being optionally substituted with one, two or three substituents, each substituent independently (Ci-C 3 )-alkyl- or -NR 6 R 7 , and
  • R 6 and R 7 represent, independently for each occurrence, a hydrogen atom or a Ci-C 3 -alkyl- group; or and R 7 , together with the nitrogen atom they are attached to, represent a 6-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a C 1 -C3- alkyl- group, a salt, tautomer, or stereoisomer of said compound, or a salt of said tautomer or stereoisomer.
  • the present invention relates to compounds of general formula (I)
  • the present invention relates to compounds of general formula (I) in which
  • R 1 represents Ci-C6-alkyl-, Ci-C6-haloalkyl-, or Ci-C6-alkoxy-;
  • R 2 represents a Ci-C3-alkyl- group
  • R 3 represents a Ci-C3-alkyl- group
  • R 4 represents a Ci-C3-alkyl- group
  • R 5 represents a chlorine atom, and salts, tautomers, or stereoisomers of said compounds, and to salts of said tautomers stereoisomers.
  • the present invention relates to compounds of general formula (I) in which
  • R represents Ci-C6-alkyl-, Ci-C6-haloalkyl-, Ci-C6-alkoxy-, Ci-C6-haloalkoxy-, or -C 1 -C6- alkyl-N(CH 3 )2,
  • R 2 represents a Ci-C3-alkyl- group
  • R 3 represents a Ci-C3-alkyl- group
  • R 4 represents a Ci-C3-alkyl- group
  • R 5 represents hydrogen, hydroxy-, -NR 6 R 7 , or a group selected from aryl-, heteroaryl-, heterocycloalkyl-, said group being optionally substituted with one, two or three substituents, each substituent independently selected from R 8 , R 6 and R 7 represent, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group; or - -
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a
  • Ci-C3-alkyl- group n is 1, 2, 3, and R 8 represents halogen-, Ci-C 3 -alkyl-, -(Ci-C 6 -alkyl)-OH, -NR 6 R 7 , -(Ci-C 6 -alkyl)-NR 6 R 7 , -0-(CH 2 ) admir-NR 6 R 7 , -(CO)-NR 6 R 7 , and salts, tautomers, or stereoisomers of said compounds, and to salts of said tautomers or stereoisomers.
  • the present invention relates to compounds of general formula (I) in which
  • R 1 represents Ci-C6-alkyl-, Ci-C6-haloalkyl-, Ci-C6-alkoxy-,
  • R 2 represents a Ci-C3-alkyl- group
  • R 3 represents a Ci-C3-alkyl- group
  • R 4 represents a Ci-C3-alkyl- group
  • R 5 represents a halogen, preferably chlorine
  • R 6 and R 7 represent, independently for each occurrence, a hydrogen atom or a Ci-C3-alkyl- group
  • R 6 and R 7 together with the nitrogen atom they are attached to, represent a 4- to 7-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a
  • Ci-C3-alkyl- group and salts, tautomers, or stereoisomers of said compounds, and to salts of said tautomers or stereoisomers.
  • the present invention relates to compounds of general formula (I) in which - -
  • R represents Ci-C6-alkyl-, Ci-C6-haloalkyl-, or Ci-C6-alkoxy-
  • the present invention relates to compounds of general formula (I) in which R 1 represents Ci-C6-alkyl-, or Ci-C6-alkoxy-.
  • the present invention relates to compounds of general formula (I)
  • R 2 , R 3 , and R 4 represent methyl.
  • the present invention relates to compounds of general formula (I), in which R 5 represents hydrogen, hydroxy-, halogen-, -NR 6 R 7 , or a group selected from aryl-, heteroaryl-, and heterocycloalkyl-, wherein said aryl-, heteroaryl-, and heterocycloalkyl- is optionally substituted with one, two or three substituents, each substituent independently selected from R 8 .
  • R 5 represents hydrogen, hydroxy-, halogen-, -NR 6 R 7 , or a group selected from aryl-, heteroaryl-, and heterocycloalkyl-, wherein said aryl-, heteroaryl-, and heterocycloalkyl- is optionally substituted with one, two or three substituents, each substituent independently selected from R 8 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents halogen, preferably chlorine.
  • the present invention relates to compounds of general formula (I), in which R 5 represents a heteroaryl- group optionally substituted with one, two or three substituents, each substituent independently selected from R 8 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents heteroaryl-, optionally substituted with one, two or three substituents, each substituent independently selected from (Ci-C3)-alkyl-, and-NR 6 R 7 .
  • the present invention relates to compounds of general formula (I), in which R 5 represents a heteroaryl- group optionally substituted with a heterocycloalkyl- group or one or two Ci-C3-alkyl- groups, wherein the heterocycloalkyl- group is optionally further substituted with a Ci-C3-alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 5 represents a heteroaryl- group optionally substituted with a 6-membered heterocycloalkyl- group or one or two Ci-C3-alkyl- groups, wherein the heterocycloalkyl- group is - -
  • Ci-C3-alkyl- group optionally further substituted with a Ci-C3-alkyl- group
  • the present invention relates to compounds of general formula (I), in which R 5 represents a 6-(4-methyl-piperazin- l-yl)pyridin-3-yl group or a 2-(4-methyl- piperazin-l-yl)pyridin-4-yl group.
  • the present invention relates to compounds of general formula (I), in which R 6 and R 7 each represent a methyl group.
  • the present invention relates to compounds of general formula (I), in which R 6 and R 7 together with the nitrogen atom they are attached to, represent a 6-membered monocyclic heterocycloalkyl- group, which is optionally substituted once with a Ci-C3-alkyl- group.
  • the present invention relates to compounds of general formula (I), in which R 6 and R 7 together with the nitrogen atom they are attached to, represent a morpholine-4-yl group or a 6-methyl-piperazine-l-yl group.
  • the present invention relates to compounds of general formula (I), in which R 8 represents Ci-C 3 -alkyl-, -(Ci-C 6 -alkyl)-OH, -NR 6 R 7 , -(Ci-C 6 -alkyl)-NR 6 R 7 , -0-(CH 2 ) contend- NR 6 R 7 , or -(CO)-NR 6 R 7 .
  • the present invention relates to compounds of general formula (I), in which R 8 represents a Ci-C3-alkyl- group or a -NR 6 R 7 group.
  • the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom.
  • Oxo may be attached to atoms of suitable valency, for example to a saturated carbon atom or to a sulfur atom.
  • Ci-Cs-alkyl- means a linear or branched, saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g., a methyl-, ethyl-, propyl-, wo-propyl-, n-butyl-, wo-butyl-, sec-butyl-, ieri-butyl-, n-pentyl-, wo-pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-, n-hexyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2-dimethylbuty
  • said group has 1, 2, 3, 4, 5 or 6 carbon atoms ("Ci-C6-alkyl-"), e.g., a methyl-, ethyl-, n-propyl-, wo-propyl-, n-butyl-, wo-butyl-, sec- butyl-, ieri-butyl-, n-pentyl-, wo-pentyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-, n-hexyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2-dimethylbutyl-, 1,1-di
  • said group has 1, 2, 3 or 4 carbon atoms ("Ci-C t-aikyl-”), e.g., a methyl-, ethyl-, n-propyl-, wo-propyl-, n-butyl-, wo-butyl-, sec-butyl- or ieri-butyl- group, 1, 2 or 3 carbon atoms ("Ci-C3-alkyl-”), e.g., a methyl-, ethyl-, n-propyl- or wo-propyl- group, or 1 or 2 carbon atoms ("Ci-C 2 -alkyl-”), e.g., a methyl-, ethyl- group.
  • C 2 -C6-alkenyl- means a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, preferably 2, 3 or 4 carbon atoms ("C 2 -C4-alkenyl-”) or 2 or 3 carbon atoms (“C 2 -C3-alkenyl-”), it being understood that in the case in which said alkenyl- group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
  • alkenyl- groups include, for example, an ethenyl-, prop-2-enyl-, (£)-prop-l-enyl-, (Z)-prop-l-enyl-, wo-propenyl-, but-3-enyl-, (£)-but-2-enyl-, (Z)-but-2-enyl-, (£)-but-l-enyl-, (Z)-but-l-enyl-, 2-methylprop-2-enyl-, l-methylprop-2-enyl-, 2-methylprop-l-enyl-, (£)-l-methylprop-l-enyl-, (3 ⁇ 4-l-methylprop-l-enyl-, buta-l,3-dienyl-, pent-4-enyl-, (£)-pent-3-enyl-, (Z)-pent-3-enyl-, (£)-pent-2-enyl-, (Z)-pent-2-
  • C2-C6-alkynyl- means a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, preferably 2, 3 or 4 carbon atoms ("C2-C4-alkynyl-") or 2 or 3 carbon atoms ("C2-C3-alkynyl-")-
  • Representative C 2 -C6-alkynyl- groups include, for example, ethynyl-, prop-l-ynyl-, prop-2-ynyl-, but-l-ynyl-, but-2-ynyl-, but-3-ynyl-, pent-l-ynyl-, pent-2-ynyl-, pent-3-ynyl-, pent-4-ynyl-, hex-l-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl
  • alkynyl- group is ethynyl-, prop-l-ynyl- or prop-2-ynyl-.
  • Ci-C6-haloalkyl- means a linear or branched, saturated hydrocarbon group in which one - -
  • Ci-C6-fluoroalkyl- groups include, for example, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 and - CH(CH 2 F) 2 .
  • C 2 -C6-haloalkenyl- means a linear or branched hydrocarbon group in which one or more of the hydrogen atoms of a "C 2 -C6-alkenyl-" as defined supra are each replaced, identically or differently, by a halogen atom.
  • said halogen atom is fluorine, resulting in a group referred herein as "C 2 -C6-fluoroalkenyl-”.
  • hydroxy-(Ci-C6-alkyl)- means a linear or branched, saturated, hydrocarbon group in which one or more hydrogen atoms of a "Ci-C6-alkyl-" as defined supra are each replaced by a hydroxy group, e.g., a hydroxy methyl-, 1 -hydroxy ethyl-, 2-hydroxyethyl-, 1,2-dihydroxyethyl-, 3- hydroxypropyl-, 2-hydroxypropyl-, 2,3-dihydroxypropyl-, l,3-dihydroxypropan-2-yl-, 3-hydroxy- 2-methyl-propyl-, 2-hydroxy-2-methyl-propyl-, or l-hydroxy-2-methyl -propyl- group.
  • Ci-C6-alkoxy- means a linear or branched, saturated, monovalent group of formula (Ci- C6-alkyl)-0-, in which the term "Ci-C6-alkyl” is as defined supra, e.g., a methoxy-, ethoxy-, n- propoxy-, wo-propoxy-, n-butoxy-, wo-butoxy-, ieri-butoxy-, seobutoxy-, pentyloxy-, wo-pentyloxy- or n-hexyloxy- group, or an isomer thereof.
  • Ci-C6-haloalkoxy- means a linear or branched, saturated, monovalent Ci-C6-alkoxy- group, as defined supra, in which one or more of the hydrogen atoms are each replaced, identically or differently, by a halogen atom.
  • said halogen atom in "Ci-C6-haloalkoxy-” is fluorine, resulting in a group referred herein as "Ci-C6-fluoroalkoxy-”.
  • Representative Ci-C6-fluoroalkoxy- groups include, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 and -OCH 2 CF 3 .
  • C 3 -Cio-cycloalkyl- means a saturated mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C 3 -Cio-cycloalkyl-")-
  • Said C 3 -Cio-cycloalkyl- group may be, for example, a monocyclic hydrocarbon ring, e.g., a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- group, or a bicyclic hydrocarbon ring, such as decalinyl-.
  • said hydrocarbon ring is monocyclic and contains 3, 4, 5, 6 or 7 carbon atoms ("C3-C7- cycloalkyl-”), e.g., a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl- group, or 3, 4, 5 or 6 carbon atoms ("C 3 -C6-cycloalkyl-”), e.g., a cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl- group.
  • a cycloalkyl group may be optionally substituted as defined at the respective part wherein such term is used.
  • heterocycloalkyl- group which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selected from oxygen, nitrogen or sulfur, and wherein carbon atoms and heteroatoms add up to 4, 5, 6, 7, 8, 9 or 10 ring atoms in total, it being possible for said heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • heterospirocycloalkyl- "heterobicycloalkyl-” and “bridged heterocycloalkyl-", as defined infra, are also included within the scope of this definition.
  • heterospirocycloalkyl- is to be understood as meaning a saturated, bicyclic hydrocarbon radical in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selected from oxygen, nitrogen or sulfur; it being possible for said heterospirocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • heterospirocycloalkyl- groups include, for example, azaspiro[2.3]hexyl-, azaspiro[3.3]heptyl-, oxaazaspiro[3.3]heptyl-, thiaazaspiro[3.3]heptyl-, oxaspiro[3.3]heptyl-, oxazaspiro[5.3]nonyl-, oxazaspiro[4.3]octyl-, oxazaspiro[5.5]undecyl-, diazaspiro[3.3]heptyl-, thiazaspiro[3.3]heptyl-, thiazaspiro[4.3]octyl-, and azaspiro[5.5]decyl-.
  • heterocycloalkyl- is to be understood as meaning a saturated, monovalent bicyclic hydrocarbon radical in which the two rings share two immediately adjacent ring atoms, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selectedfrom oxygen, nitrogen or sulfur; it being possible for said heterobicycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • heterobicycoalkyl- groups include, for example, azabicyclo[3.3.0]octyl-, azabicyclo[4.3.0]nonyl-, diazabicyclo[4.3.0]nonyl-, oxazabicyclo[4.3.0]nonyl-, thiazabicyclo[4.3.0]nonyl-, and azabicyclo[4.4.0]decyl-.
  • bridged heterocycloalkyl- is to be understood as meaning a saturated, monovalent bicyclic hydrocarbon radical in which the two rings share two common ring atoms which are not immediately adjacent, and wherein said bicyclic hydrocarbon radical contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms preferably selected from oxygen, nitrogen and sulfur; it being possible for said bridged heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Exemplary bridged heterocycloalkyl- groups include, for example, azabicyclo[2.2.1]heptyl-, oxazabicyclo[2.2.1]heptyl-, thiazabicyclo[2.2.1]heptyl-, diazabicyclo[2.2.1]heptyl-, azabicyclo[2.2.2]octyl-, diazabicyclo[2.2.2]octyl-, - -
  • said "4- to 10-membered heterocycloalkyl-" is monocyclic and contains 3, 4, 5 or 6 carbon atoms, and one or two of the above-mentioned heteroatoms, adding up to 4, 5, 6 or 7 ring atoms in total (a "4- to 7-membered monocyclic heterocycloalkyl-"), or contains 3, 4 or 5 carbon atoms, and one or two of the above-mentioned heteroatoms, adding up to 4, 5 or 6 ring atoms in total (a "4- to 6-membered monocyclic heterocycloalkyl-"), or contains 3, 4 or 5 carbon atoms, and one or two of the above-mentioned heteroatoms, adding up to 5 or 6 ring atoms in total (a "5- to 6-membered monocyclic heterocycloalkyl-"); it being possible for said heterocycloalkyl- group to be attached to the rest of the molecule via any one of the carbon atoms or the nitrogen atoms,
  • said "4- to 7-membered monocyclic heterocycloalkyl-" can be a 4-membered ring, a "4-membered heterocycloalkyl-", such as azetidinyl- or oxetanyl-; or a 5-membered ring, a "5-membered heterocycloalkyl-", such as tetrahydrofuranyl-, dioxolinyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl- or pyrrolinyl-; or a 6- membered ring, a "6-membered heterocycloalkyl-", such as tetrahydropyranyl-, piperidinyl-, morpholinyl-, dithianyl-, thiomorpholinyl- or piperazinyl-; or a 7-membered ring, a "7-membered heterocycloalkyl-", such
  • heteroaryl- means a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl-" group), preferably 5, 6, 9 or 10 ring atoms, and which contains 1, 2, 3 or 4 heteroatoms which may be identical or different, said heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • Said heteroaryl- group can be a 5-membered heteroaryl- group, such as, for example, thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl- or tetrazolyl-; or a 6-membered heteroaryl- group, such as, for example, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl- or triazinyl-; or a benzo-fused 5-membered heteroaryl- group, such as, for example, benzofuranyl-, benzothienyl-, benzoxazolyl-, benzisoxazolyl-, benzimidazolyl-, benzothiazoly
  • indolizinyl- such as, for example, indolizinyl-, purinyl- or pteridinyl-; or a tricyclic heteroaryl- group, such as, for example, carbazolyl-, acridinyl- or phenazinyl-.
  • heteroaryl- is a monocyclic aromatic ring system having 5 or 6 ring atoms and which contains at least one heteroatom, if more than one, they may be identical or different, said heteroatom being selected from the group consisting of oxygen, nitrogen and sulfur ("5- to 6- membered monocyclic heteroaryl-”), such as, for example, thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl- or triazinyl-.
  • oxygen nitrogen and sulfur
  • heteroaryl- groups include all the possible isomeric forms thereof, e.g., the positional isomers thereof.
  • pyridyl- includes pyridin-2-yl-, pyridin-3-yl- and pyridin-4-yl-
  • thienyl- includes thien-2-yl- and thien-3-yl-.
  • heteroaryl- groups can be attached to the rest of the molecule via any one of the carbon atoms, or, if applicable, a nitrogen atom, e.g., pyrrol- l-yl-, pyrazol-l-yl- or imidazol-l-yl-.
  • the term "leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons, e.g., typically forming an anion.
  • a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-,
  • Ci-Ce as used throughout this text, e.g., in the context of the definition of "Ci-C6-alkyl-", “Ci-C6-haloalkyl-", “Ci-C6-alkoxy-” or “Ci-C6-haloalkoxy-” is to be understood as meaning an alkyl group having a whole number of carbon atoms from 1 to 6, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “Ci-Ce” is to be interpreted as disclosing any sub-range comprised therein, e.g.
  • Ci-Ce Ci-Ce , C2-C5 , C3-C4 , C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; preferably C1-C2 , C1-C3 , C1-C4 , C1-C5 , C1-C6 ; more preferably C1-C4 ; in the case of "C1-C6- haloalkyl-" or "Ci-C6-haloalkoxy-" even more preferably C 1 -C 2 .
  • C 2 -C6 as used throughout this text, e.g., in the context of the definitions of "C 2 -C6-alkenyl-” and “C 2 -C6-alkynyl-”, is to be understood as meaning an alkenyl- group or an alkynyl group having a whole number of carbon atoms from 2 to 6, i.e., 2, 3, 4, 5 or 6 carbon atoms.
  • C2-C6 is to be interpreted as disclosing any sub-range comprised therein, e.g., d- e , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; preferably C2-C3. - -
  • C3-C7 as used throughout this text, e.g., in the context of the definition of "C3-C7-cycloalkyl-”, is to be understood as meaning a cycloalkyl- group having a whole number of carbon atoms of 3 to 7, i.e., 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term “C3-C7” is to be interpreted as disclosing any sub-range comprised therein, e.g., C 3 -C 6 , C4-C5 , C3-C5 , C3-C4 , C 4 -C 6 , C5-C7 ; preferably C 3 -C 6 .
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g., a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of this invention may contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds (atropisomerism).
  • Substituents on sp 3 carbons in a ring may also be disposed in either cis or trans dispositions relative to each other. It is intended that all such configurations are included within the scope of the present invention.
  • Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated - -
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials, enantioselective catalytic reactions, and other suitable methods.
  • the compounds of the present invention may exist as tautomers.
  • any compound of the present invention which contains a 2-pyridone moiety can exist as a 2- hydroxypyridine tautomer, or a 2-pyridone tautomer, or even a mixture in any amount of the two tautomers:
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), U C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 131 I, respectively. Accordingly, recitation of "hydrogen” or “H” should be understood to encompass 3 ⁇ 4 (protium), 2 H (deuterium), and 3 H (tritium) unless otherwise specified.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies.
  • Tritiated and carbon- 14, i.e. , 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also concerns other forms related to the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention form a crystal that contains molecules of polar solvents, in particular water, methanol or ethanol, for example, as structural element of the crystal lattice of the compounds.
  • the molecules of polar solvents, in particular water may be present in a stoichiometric or non-stoichiometric ratio with the molecules of the compound.
  • solvates e.g., a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system are covered by the invention.
  • Said biological system may be, for example, a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
  • the compounds of the present invention can exist in free form, e.g., as a free base or a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • Salts which are preferred for the purposes of administration are physiologically acceptable salts of the compounds according to the invention.
  • salts which are not suitable for pharmaceutical applications per se, but which, for example, can be used for the isolation or purification of the compounds according to the invention are also part of the present invention.
  • Physiologically acceptable salts of the compounds according to the invention encompass acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, hydroiodic, sulfuric acid, bisulfuric acid, phosphoric acid, nitric acid or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3- phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic
  • Physiologically acceptable salts of the compounds according to the invention also comprise salts of conventional bases, such as, by way of example and by preference, alkali metal salts (for example lithium, sodium and potassium salts), alkaline earth metal salts (for example calcium, strontium and magnesium salts), other salts (such as, e.g., aluminium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C atoms, such as, by way of example and by preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, -mefhylmorpholine, arginine, lysine, ethylenediamine, /V-methylpiperidine, N- methylglucamine, dimethylglucamine, ethylgluc
  • the compounds according to the invention may form salts with a quaternary ammonium ion obtainable, e.g., by quaternisation of a basic nitrogen-containing group with agents such as lower alkylhalides such as methyl-, ethyl-, propyl-, and butylchlorides, -bromides and -iodides ; dialkylsulfates such as dimethyl-, diethyl-, dibutyl- and diamylsulfates; long chain halides such as decyl-, lauryl-, myristyl- and stearylchlorides, -bromides and -iodides; aralkylhalides such as benzyl- and phenethylbromides and others.
  • agents such as lower alkylhalides such as methyl-, ethyl-, propyl-, and butylchlorides, -bromides and -iodides ; dial
  • quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra( «-propyl)ammonium, tetra (n-butyl)ammonium, or -benzyl-AW -trimethylammonium.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio. - 7 -
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the Suzuki coupling reaction is catalyzed by palladium catalysts, such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] , tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3] , dichlorobis(triphenylphosphine)-palladium(II) [Pd(PPli3)2Cl2], palladium(II) acetate and triphenylphosphine,by [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride, or by palladacycle precatalysts known to the person skilled in the art, for example chloro(2-di- cyclohexylphosphino-2',6'-diisopropoxy- 1, 1 '-biphenyl) [2-(2'-amino- 1 , 1 '-b
  • the reaction is carried out in solvents selected from water, 1,2-dimethoxyethane, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, A ⁇ -dimefhylacetamide, 7V-mefhylpyrrolidin-2-one, tetrahydrofuran, and an aliphatic alcohol of the formula Ci-C 3 -alkyl-OH, or a mixture containing two or more of said solvents, preferably a mixture of two solvents selected from ethanol, toluene and 1,2-dimethoxyethane, optionally containing up to 20 v/v % of water, more preferred a mixture of toluene and ethanol, optionally containing up to 10 v/v % of water, or a mixture of toluene and 1,2-dimethoxyethane, optionally containing up to 10 v/v % of water.
  • solvents selected from water, 1,2-dimethoxyethane,
  • the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate, in solid form or in aqueous solution in a concentration ranging from 0.25 N to 3 N, preferably potassium phosphate in aqueous solution in a concentration ranging from 0.3 - -
  • N to 1 N more preferably potassium phosphate in aqueous solution in a concentration ranging from 0.3 N to 0.7 N.
  • the reaction is carried out in a temperature range between 60°C and 180°C, preferably 70°C and 120°C, more preferably 75°C and 100 °C, over a time between 15 minutes and 24 hours, preferably 30 minutes and 4 hours, preferably under an atmosphere of argon, in a microwave oven or in an oil bath.
  • Said 4-chloroquinoline-7-carboxamide derivates of formula (IV) can, in turn, be assembled from 3- aminomethyl pyridone derivatives of formula (II), in which R 1 and R 2 are as defined for the compounds of general formula (I), and 4-chloroquinoline-7-carboxylic acid derivatives of formula ( ⁇ ), in which R 3 and R 4 are as defined for the compounds of general formula (I), by means of carboxamide (or peptide) coupling reaction well known to the person skilled in the art, according to Scheme la.
  • Said coupling reaction can be performed by reaction of compounds of the formulae (II) and (III) in the presence of a suitable coupling reagent, such as HATU (0-(7-azabenzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (0-(benzotriazol-l-yl)-N,/V,N',N'- tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate), T3P (2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide), or EDC (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOBt (1 -hydroxy-
  • compounds of general formula (I) can also be assembled from 3-aminomethyl pyridone derivatives of formula (II), in which R 1 and R 2 are as defined for the compounds of general formula (I), and quinoline-7-carboxylic acid derivatives of formula (VI), in which R 3 , R 4 and R 5 are as defined for the compounds of general formula (I), by means of carboxamide (or peptide) coupling reaction well known to the person skilled in the art, according to Scheme lb.
  • Said coupling reaction can be performed by reaction of compounds of the formulae (II) and (VI) in the presence of a suitable coupling reagent, such as HATU (0-(7-azabenzotriazol-l-yl)-A',/V,/V',/V'- tetramethyluronium hexafluorophosphate), TBTU (0-(benzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyl- uronium tetrafluoroborate), PyBOP (benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate), T3P (2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide), or EDC (l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in combination with HOB
  • Preferred herein is the performance of said carboxamide coupling reaction using 0-(7-azabenzotriazol-l-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate (HATU) as a coupling agent, in the presence of /V,/V-diisopropylethylamine as a base, and in -dimethylformamide as a solvent, within a temperature range from 0°C to 50°C. - -
  • Scheme lc outlines the synthesis of 4-amino-quinoline-7-carboxamides of general formula (XIII), which are compounds of formula (I), in which R 1 , R 2 , R 3 and R 4 are as defined for the compounds of general formula (I) and R 5 represents a group N(R 6 )R 7 as defined for the compounds of general formula (I), starting from 4-chloro quinoline-7-carboxamides of formula (IV).
  • 4-Chloro quinoline- 7-carboxamides of formula (IV) can be reacted with a suitable primary or secondary amine of general formula (XII) in solvents such as dioxane, -mefhyl-pyrrolidone, dimethylsulfoxide or N-dimefhylformamide under elevated temperature and/or by palladium(O) catalysis, preferably by using tris(dibenzylideneacetone)dipalladium(0) and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene in the presence of a base, preferably cesium carbonate.
  • a base preferably cesium carbonate.
  • 4-chloro quinoline-7-carboxamides 4-alkylsulfonate quinoline-7-carboxamides or 4-bromo quinoline-7- carboxamides can be applied.
  • 3-Aminomethyl pyridone derivatives and quinoline-7-carboxylic acids of formulae (II), (III) and (VI) can be prepared using synthetic methods described in more detail as according to Schemes 2a, 2b, 3a, 3b, 3c, 3d, 3e, 4a and 4b, shown below. - -
  • Scheme 2a displays a synthesis route which can be used for the preparation of quinoline-7- carboxylic acids of formula (III), in which R 3 and in which R 4 are as defined for the compounds of general formula (I) and which constitutes a sub-compartment of formula (III).
  • R 3 substituted 3-aminobenzoates in which R E represents a Ci-C3-alkyl- group, preferably a methyl- or ethyl- group by reaction with 3-oxobutanoates in which R E also represents a C 1 -C3- alkyl- group, preferably a methyl- or ethyl- group under conversion into 4-hydroxy quinoline-7- carboxylates (IX) in the presence of an acid such as p-toluene sulfonic acid in an inert solvent, preferably toluene.
  • R E represents a Ci-C3-alkyl- group, preferably a methyl- or ethyl- group by reaction with 3-oxobutanoates in which R E also represents a C 1 -C3- alkyl- group, preferably a methyl- or ethyl- group under conversion into 4-hydroxy quinoline-7- carboxylates (IX) in the presence of an acid such as p
  • Conversion of 4-hydroxy quinoline-7-carboxylates (IX) to 4-chloro quinoline- 7-carboxylic acids of formula (X) can be done using trichlorophosphate pure or in solution with toluene, thionyl chloride in /V,/V-dimethyl formamide, preferably trichlorophosphate.
  • Saponification of carboxylic esters of formula (X) can be performed using an alkali hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, in an aqueous aliphatic alcohol of the formula (Ci-C3-alkyl)-OH, optionally additionally containing a cyclic ether such as tetrahydrofuran, as a solvent, as well known to the person skilled in the art, to give rise to the desired 4-chloro quinoline-7-carboxylic acids of formula (III).
  • an alkali hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide
  • an aqueous aliphatic alcohol of the formula (Ci-C3-alkyl)-OH optionally additionally containing a cyclic ether such as tetrahydrofuran, as a solvent, as well known to the person skilled in the art, to give rise to the desired 4-chloro quinoline-7-carboxylic acids of formula (III).
  • Quinoline-7 -carboxylic acids and their esters of formula (VI) and (XI) are available from 4-chloro quinoline-7-carboxylic acids of formulae (III) or the corresponding carboxylic esters (X), in which R E represents a Ci-C3-alkyl- group, and boronic acid derivatives R 5 -B(OR)2 of formula (V), in which R 5 is as defined for the compound of general formula (I), and in which R represents a hydrogen atom or a Ci-C3-alkyl- group, or R-R together represent a -C2-C6-alkylene- group, by means of a palladium catalysed Suzuki coupling reaction well known to the person skilled in the art, according to Scheme 2b, in an analogous fashion as described for the conversion of 4-chloro quinoline-7-carboxamides of formula (IV) into compounds of general formula (I) in context of Scheme la, supra.
  • carboxylic esters of formulae (X) are employed, carboxylic esters of formula (XI) are formed initially can be cleaved by methods known to the person skilled in the art, in a similar fashion as discussed supra for the conversion of quinoline-7-carboxylic acid esters (XI) into quinoline-7- carboxylic acids (Scheme 2a).
  • Schemes 3a, 3b, 3c, 3d and 3e display synthesis routes suitable for the preparation of 3- aminomethyl pyridone intermediates of formulae (Ila), (lib), (lie), all of them constituting sub- compartments of the formula (II) shown supra. - -
  • Scheme 3a illustrates the synthesis of 3-aminomethyl pyridone intermediates of formula (Ila), in which R l represents a group selected from the groups representing R 1 as defined for the compounds of general formula (I) which is linked to the pyridone ring via a carbon atom, e.g. Ci- C3-alkyl-, Ci-C3-haloalkyl- or benzyl- group, and in which R 2 represents a Ci-C3-alkyl- group, and their salts, e.g.
  • hydrochloride, hydrobromide or trifluoroacetate salts preferably hydrochloride salts, from ⁇ , ⁇ -unsaturated ketones of formula (XIX), which can be reacted with 2-cyanoacetamide (XX; see also e.g.
  • WO 2011/140325 in the presence of a suitable base, such as an aliphatic amine, preferably piperidine, in an aliphatic alcohol of the formula (Ci-C 3 -alkyl)-OH, preferably ethanol, or, alternatively, in the presence of an alkoxide of an alkali metal, preferably potassium tert- butoxide, as a base, and in dimethyl sulfoxide as a solvent, to give 2-oxo-l,2-dihydropyridine-3- carbonitriles of formula (XXI).
  • a suitable base such as an aliphatic amine, preferably piperidine
  • an aliphatic alcohol of the formula (Ci-C 3 -alkyl)-OH preferably ethanol
  • an alkoxide of an alkali metal preferably potassium tert- butoxide
  • Said 2-oxo-l,2-dihydropyridine-3-carbonitriles of formula (XXI) can subsequently be reduced to 3-aminomethyl pyridone derivatives of formula (Ila) by methods known to the person skilled in the art, such as by reaction with hydrogen gas in the presence of palladium(II)hydroxide (Pd(OH) 2 ) in methanol containing aqueous hydrochloric acid, or by reaction with hydrogen gas in the presence of Raney Nickel in /V,/V-dimethylformamide as a solvent.
  • Pd(OH) 2 palladium(II)hydroxide
  • Raney Nickel Raney Nickel in /V,/V-dimethylformamide
  • concomitant formation of regioisomers of formula (XXIa) may occur.
  • Said regioisomers can be separated either immediately after their formation, or at a later stage, by methods well known to the person skilled in the art, exemplified by but not limited to the introduction of a ieri-butoxycarbonyl group onto the aminomethyl group present in compounds of the formula (Ila) and their regioisomers, followed by isomer separation by means of column chromatography or preparative HPLC, and removal of the ieri-butoxycarbonyl group as illustrated in the experimental section (see e.g. protocols of intermediates 143 A and 144A).
  • the resulting 3-aminomethyl pyridone intermediates of formula (Ila) can be isolated as free bases, or, depending on the reaction conditions in the final step, and/or the work-up procedure, as salts, e.g. hydrochloride, hydrobromide or trifluoroacetate salts.
  • the intermediates of formula (Ila) are isolated as hydrochloride salts.
  • the ⁇ , ⁇ -unsaturated ketones of formula (XIX) used as starting material are well known to the person skilled in the art and commercially available in certain cases, see also Scheme 4a for less common starting materials of formula (XIX).
  • Scheme 3b illustrates the synthesis of 3-aminomethyl pyridone intermediates of formula (lib), in which R lb represents a group selected from the groups representing R 1 as defined for the compounds of general formula (I) which is linked to the pyridone ring via a carbon atom, e.g. a (Ci-C3-alkoxy)-(Ci-C3-alkyl)- or Ci-C3-haloalkyl- group, and in which R 2 represents a Ci-C3-alkyl- group, and their salts, e.g.
  • a suitable base such as an aliphatic amine, preferably piperidine
  • an aliphatic alcohol of the formula (Ci-C3-alkyl)-OH preferably ethanol
  • the resulting 3-aminomethyl pyridone intermediates of formula (lib) can be isolated as free bases, or, depending on the reaction conditions in the final step, and/or the work-up procedure, as salts, e.g. hydrochloride, hydrobromide or trifluoroacetate salts.
  • salts e.g. hydrochloride, hydrobromide or trifluoroacetate salts.
  • R lc represents a group selected from the groups representing R 1 as defined for the compounds of general formula (I) which is linked to the pyridone ring via an oxygen atom, e.g. a Ci-C3-alkoxy- or Ci-C3-haloalkoxy- group, or a (C3-C7-cycloalkyl)-(L 1 )- group in which L 1 represents -CH2O- or -0-, and in which R 2 represents a methyl- group, as outlined in Schemes 3c, 3d and 3e.
  • Scheme 3c illustrates the preparation of said 3-aminopyridone intermediates of formula (He) starting from ethyl 2,4-dihydroxynicotinate (CAS-No. 10350-10-4; XXIV) which can be selectively benzylated at 2-OH using benzyl bromide and silver carbonate in tetrahydrofuran to give monobenzyl ether (XXV), which, in turn, can be reacted with a compound of formula (XXVI), in which R lc represents e.g.
  • Reduction of the azide group with concomitant cleavage of the benzyl ether present in azides of formula (IXXX) can be achieved using methods well known to the person skilled in the art, such as reaction with hydrogen gas in the presence of palladium on carbon in an aliphatic alcohol of the formula (C1-C3- alkyl)-OH, preferably methanol, or in the presence of palladium(II) hydroxide, in a mixture comprising an aliphatic alcohol of the formula (Ci-C3-alkyl)-OH, preferably ethanol, and an aliphatic carboxylic acid of the formula (Ci-C2-alkyl)-C(0)OH, preferably acetic acid, under elevated hydrogen pressure if needed, and optionally followed by treatment with an acid, to yield 3-aminomethyl pyridone intermediates of formula (lie) either as free base or as salt, preferably as hydrochloride salt.
  • Scheme 3d illustrates an alternative preparation of said 3-aminomethylpyridone intermediates of formula (He) starting from commercially available 4-methyleneoxetan-2-one (XXX), which can be - -
  • XXXI 2-amino-6-mefhyl-4-oxo- 4H-pyran-3-carbonitrile
  • XXXII 2-amino-6-mefhyl-4-oxo- 4H-pyran-3-carbonitrile
  • XXXII 2,4-dihydroxy-6- methylnicotinonitrile
  • XXXIII 2,4- dichloro-6-methylnicotinonitrile
  • Scheme 4a describes a synthetic approach to starting materials of formula (XIX) which are not commercially available, by methods which however are well known to the person skilled in the art.
  • Carboxylic esters of formula (XXXIX) in which R l represents e.g. a Ci-C 3 -alkyl-, C 1 -C3- haloalkyl- or benzyl- group, and in which R E represents a Ci-C 3 -alkyl- group, can be readily converted into the corresponding aldehydes (XL) using well-known standard reduction and oxidation protocols (e.g.
  • aldehydes can be subjected to a Wittig olefination using phosphoranes of formula (XLI), in which R 2 represents a Ci-C3-alkyl- group, to give ⁇ , ⁇ - unsaturated ketones of formula (XIX).
  • carboxylic esters of formula (XXXIX) can be directly converted into ⁇ , ⁇ -unsaturated ketones of formula (XIX) by reaction with methyl ketones of formula (XLII), in which R 2 represents a Ci-C 3 -alkyl- group, in the presence of an alkali amide, e.g. sodium amide.
  • an alkali amide e.g. sodium amide.
  • Scheme 4b describes the synthesis of starting materials of formula (XXII) which are not commercially available. They can be readily prepared by reacting commercially available carboxylic esters of formula (XXXIXa) in which R lb represents e.g. a (Ci-C3-alkoxy)-(Ci-C3- alkyl)- or Ci-C3-haloalkyl- group, and in which R E represents a Ci-C3-alkyl- group, with a methyl ketone of formula (XLII) and a metal hydride, such as sodium hydride.
  • R lb represents e.g. a (Ci-C3-alkoxy)-(Ci-C3- alkyl)- or Ci-C3-haloalkyl- group
  • R E represents a Ci-C3-alkyl- group
  • a metal hydride such as sodium hydride.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate compound of formula (IV)
  • R 5 is aryl-, heteroaryl-, or heterocycloalkyl-, wherein said aryl-, heteroaryl-, or heterocycloalkyl-1 is optionally substituted with one, two or three substituents, each substituent independently selected from R 8 ; and in which R represents a hydrogen atom or a Ci-C3-alkyl- group, or both occurrences of - -
  • R taken together represent a -C2-C6-alkylene- group; thus providing a compound of general formula (I) :
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra.
  • the present invention relates to a method of preparing compounds of general formula (I), in which method an intermediate compound of formula (VI):
  • R 3 , R 4 , and R are as defined for the compounds of general formula (I), supra, and in case of substitutents bearing or representing a hydroxy- or amino- group, said group may be protected under conditions known to those with ordinary skill (see T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4th edition, Wiley 2006) ; is allowed to react with a compound of formula (II):
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra.
  • the present invention relates to a method of preparing compounds of general formula (I) wherein R 5 is chlorine; said method comprising the step of allowing an intermediate of general formula (II):
  • Compounds of formula (IV) are compounds of general formula (I) as well as intermediate compounds useful for the synthesis of compounds of formula (I) wherein R 5 is different from chlorine as disclosed herein.
  • the present invention relates to a method of preparing compounds of general formula (I), supra; in which method an intermediate compound of formula (IV):
  • the present invention relates to intermediate compounds which are useful for the preparation of compounds of the present invention of general formula (I), particularly in the methods described herein.
  • the present invention relates to intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the methods described herein.
  • R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra; as well as to the method of using intermediate compound (VI) for the preparation of compounds of general formula (I).
  • the present invention relates to the use and a method of using of the intermediate compounds of formula (IV):
  • the present invention covers the use and a method of using of the intermediate compounds of formula (IV): - -
  • the present invention provides the use and a method of using of the intermediate compounds of formula (II):
  • R 1 and R 2 are as defined for the compounds of general formula (I), supra; for the preparation of a compound of general formula (I) as defined supra.
  • the present invention covers the use and a method of using of the intermediate compounds of formula (III):
  • the compounds according to general formula (I) have valuable pharmaceutical properties which make them commercially utilizable.
  • the compounds of the formula (I) inhibit PRC2, especially EZH2, its mechanism being explained in the Background section, and exhibit cellular activity. They are expected to be commercially applicable in the treatment of diseases (e.g., characterized by activation of PRC2).
  • one aspect of the present invention is the use of the compounds of formula (I) for the treatment of diseases.
  • Another aspect of the present invention is a compound of formula (I) for use in the treatment of a disease/diseases.
  • the compounds of general formula (I) are suitable for prophylaxis and/or treatment of hyperproliferative disorders, for example, psoriasis, keloids and other hyperplasias which affect the skin, benign prostate hyperplasias (BPH), solid tumors and haematological tumors.
  • hyperproliferative disorders for example, psoriasis, keloids and other hyperplasias which affect the skin, benign prostate hyperplasias (BPH), solid tumors and haematological tumors.
  • another apect of the invention is the use of the compounds of formula (I) for prophylaxis and/or treatment of hyperproliferative diseases, especially for treatment of neoplastic diseases, more specifically cancer.
  • prophylaxis includes a use of the compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample, when administered to prior to the onset of the disorder or condition.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of hyperproliferative diseases.
  • Another aspect of the invention is a method of inhibiting proliferation of a cell, comprising contacting the cell with a compound of formula (I).
  • a further aspect is the method of prophylaxis and/or treatment of hyperproliferative diseaes comprising administering an effective amount of one or more compound(s) of formula (I), especially a method of treatment of a hyperproliferative disease.
  • the compounds of formula (I) are also suitable for prophylaxis and/or treatment of benign - -
  • hyperproliferative diseases for example endometriosis, leiomyoma and benign prostate hyperplasia.
  • the hyperproliferative disease is a benign hyperproliferative disease.
  • Another aspect of the present invention is a compound of formula (I) for use in the treatment of cancer. They are particular useful in treating metastatic or malignant tumors.
  • Another aspect of the invention is a method of treatment of cancer comprising administering an effective amount of at least one compound of formula (I).
  • Another aspect of the invention is the use of the compounds of formula (I) for the treatment of cancer.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of cancer.
  • a further aspect of the invention is a method of treatment of a metastatic or malignant tumor comprising administering an effective amount of a compound of formula (I).
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of a solid tumor.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of a solid tumor.
  • a further aspect of the invention is a method of treatment of a solid tumor comprising administering an effective amount of a compound of formula (I).
  • solid tumors that can be treated as, for example, tumors of the breast, the respiratory tract, the brain, the bones, the central and peripheral nervous system, the colon, the rectum, the anus, the reproductive organs (e.g., cervix, ovary, prostate), the gastrointestinal tract, the urogenital tract, the endocrine glands (e.g., thyroid and adrenal cortex), the thyroid gland, the parathyroid gland, the esophagus, the endometrium, the eye, the germ cells, the head and the neck, the kidney, the liver, the larynx and hypopharynx, the lung, the mesothelioma, the pancreas, the prostate, the rectum, the kidney, the small intestine, the skin, the soft tissue, the stomach, the testis, ureter, vagina and vulva and the connective tissue and metastases of these tumors.
  • Malignant neoplasias include inherited cancers exemplified by
  • Still another aspect of the invention is a method of treatment of a tumor mentioned above comprising administering an effective amount of a compound of formula (I).
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of a - -
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of a hematological tumor.
  • a further aspect of the invention is a method of treatment of a hematological tumor comprising administering an effective amount of a compound of formula (I).
  • Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplasia syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS -related malignancies.
  • Still another aspect of the invention is a method of treatment of a hematological tumor mentioned above comprising administering an effective amount of a compound of formula (I).
  • a further aspect of the invention is a method of administering to a subject having a cancer expressing a mutant EZH2 (e.g. , tyrosine 641, alanine 677 and/or alanine 687 mutant EZH2) a therapeutically effective amount of the compound of formula (I), wherein the compound inhibits histone methyltransferase activity of PRC2, thereby treating the cancer.
  • a mutant EZH2 e.g. , tyrosine 641, alanine 677 and/or alanine 687 mutant EZH2
  • this invention relates to a method of administering to a subject having a cancer expressing a loss of function mutation in the H3K27 demethylase KDM6A/UTX (e.g., medulloblastoma, bladder cancer, T-cell acute lymphoblastic leukemia) a therapeutically effective amount of the compound of formula (I), wherein the compound inhibits histone methyltransferase activity of PRC2, thereby treating the cancer.
  • a cancer expressing a loss of function mutation in the H3K27 demethylase KDM6A/UTX e.g., medulloblastoma, bladder cancer, T-cell acute lymphoblastic leukemia
  • Another aspect of the invention is the use of a compound of formula (I) for the treatment of a subject having a cancer with aberrant H3K27 methylation.
  • aberrant H3K27 methylation may include a genome-wide increase and/or a gene-specific altered distribution of H3K27 mono-, di- or trimethylation within the cancer cell chromatin.
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of a subject having a cancer with a mutation in a gene of the SWI/SNF chromatin remodeling complex proteins.
  • SWI/SNF complex has been described to have antagonizing PRC2 complex activities.
  • SWI/SNF chromatin remodeling complex genes examples include SMARCB 1/INI mutations (e.g., found in malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors), ARID1A mutations (e.g., found in endometrial, ovarian, or uterine cancers), SS 18-SSX fusion protein caused by the t(X;18)(pl l .2;ql l .2) translocation in synovial sarcoma, and SMARCA4 mutations (e.g., found in lung, bladder, or colorectal cancer).
  • SMARCB 1/INI mutations e.g., found in malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors
  • ARID1A mutations e.g., found in endometrial, ovarian, or uterine cancers
  • SS 18-SSX fusion protein caused by the t
  • Breast tumors that can be treated include, for example, mammary carcinoma with positive hormone receptor status, mammary carcinoma with negative hormone receptor status, Her-2-positive mammary carcinoma, hormone receptor- and Her-2-negative mammary carcinoma, BRCA- associated mammary carcinoma and inflammatory mammary carcinoma.
  • Tumors of the respiratory tract that can be treated include, for example, non-small-cell bronchial carcinoma and small-cell bronchial carcinoma, non-small cell lung cancer, and small cell lung cancer.
  • Brain tumors that can be treated include, for example, glioma, glioblastoma, astrocytoma, meningioma and medulloblastoma.
  • Tumors of the male reproductive organs that can be treated include, for example, prostate carcinoma, malignant epididymal tumors, malignant testicular tumors and penile carcinoma.
  • Tumors of the female reproductive organs that can be treated include, for example, endometrial carcinoma, cervical carcinoma, ovarian carcinoma, vaginal carcinoma and vulvar carcinoma.
  • Tumors of the gastrointestinal tract that can be treated include, for example, colorectal carcinoma, anal carcinoma, gastric carcinoma, pancreatic carcinoma, oesophageal carcinoma, gallbladder carcinoma, small-intestinal carcinoma, salivary gland carcinoma, neuroendocrine tumors and gastrointestinal stromal tumors.
  • Tumors of the urogenital tract that can be treated include, for example, urinary bladder carcinoma, renal cell carcinoma, and carcinoma of the renal pelvis and of the urinary tract.
  • Tumors of the eye that can be treated include, for example, retinoblastoma and intraocular melanoma.
  • Tumors of the liver that can be treated include, for example, hepatocellular carcinoma and cholangiocellular carcinoma.
  • Tumors of the skin include, for example, malignant melanoma, basalioma, spinalioma, Kaposi's sarcoma and Merkel cell carcinoma.
  • Tumors of the head and neck that can be treated include, for example, laryngeal carcinoma and carcinoma of the pharynx and of the oral cavity.
  • Sarcomas that can be treated include, for example, soft tissue sarcoma, synovial sarcoma, rhabdoid sarcoma and osteosarcoma.
  • Lymphomas that can be treated include, for example, non-Hodgkin's lymphoma, Hodgkin's lymphoma, cutaneous lymphoma, lymphoma of the central nervous system and AIDS-associated - -
  • lymphoma lymphoma
  • Leukaemias that can be treated include, for example, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chronic lymphatic leukaemia and hair cell leukaemia.
  • the compounds of formula (I) can be used for prophylaxis and/or treatment of Bladder cancer, Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL-rearranged leukemia, Lung adenocarcinomas, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumors, Synovial sarcoma, Teratoid/rhabdoid tumors, or T-cell acute lymphoblastic leukemia.
  • another aspect of the invention is the use of a compound of formula (I) for the treament of Bladder cancer, Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL-rearranged leukemia, Lung adenocarcinoma, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumor, Synovial sarcoma, Teratoid/rhabdoid tumor, or T-cell acute lymphoblastic leukemia.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of Bladder cancer, Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL- rearranged leukemia, Lung adenocarcinoma, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumor, Synovial sarcoma, Teratoid/rhabdoid tumor, or T-cell acute lymphoblastic leukemia tumor.
  • a further aspect of the invention is a method of treatment of Bladder cancer, Brain cancer, Breast cancer, Colorectal cancer, Chronic myelomonocytic leukemia, MLL-rearranged leukemia, Lung adenocarcinoma, Lymphoma, Medulloblastoma, Melanoma, Multiple myeloma, Prostate cancer, Malignant rhabdoid tumor, Synovial sarcoma, Teratoid/rhabdoid tumor, or T-cell acute lymphoblastic leukemia tumor comprising administering an effective amount of a compound of formula (I).
  • the compounds of formula (I) can be used for prophylaxis and/or treatment of Breast cancer.
  • Another aspect of the invention is the use of a compound of formula (I) for the treament of Breast cancer.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of Breast cancer.
  • a further aspect of the invention is a method of treatment of Breast cancer comprising administering an effective amount of a compound of formula (I). - -
  • the compounds of formula (I) can be used for prophylaxis and/or treatment of mammary carcinoma, particularly for the treatment.
  • Another aspect of the invention is the use of a compound of formula (I) for the treatment of mammary carcinoma.
  • a further aspect of the invention is the compound of formula (I) for use in the treatment of mammary carcinoma.
  • a further aspect of the invention is a method of treatment of mammary carcinoma comprising administering an effective amount of a compound of formula (I).
  • the present application further provides the compounds of formula (I) for use as medicaments, especially for prophylaxis and/or treatment of a neoplastic disorder.
  • the invention further provides for the use of the compounds of formula (I) for production of a medicament.
  • a further aspect of the invention is a method of using the compound of formula (I) for the production of a pharmaceutical composition.
  • the present invention further provides for the use of the inventive compounds for production of a medicament for prophylaxis and/or treatment of a neoplastic disorder.
  • the present application further provides for the use of the inventive compounds for prophylaxis and/or treatment of a neoplastic disorder.
  • the invention further provides for the use of the inventive compounds for treatment of a benign hyperplasia, inflammation disorder, autoimmune disorder, sepsis, viral infection, vascular disorder or neurodegenerative disorder.
  • compositions comprising at least a compound of general formula (I) together with one or more excipients, e.g. , pharmaceutically acceptable exipients, especially for the treatment and/or prophylaxis of the diseases mentioned above.
  • the invention relates to a method of treatment according to any one of a method disclosed herein comprising administering a pharmaceutical composition comprising a compound of general formula (I) together with one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising a compound of general formula (I) together with one or more pharmaceutically acceptable excipients.
  • the compounds of general formula (I) may be utilized, as such or in compositions, in - -
  • the compounds according to the invention may have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, orally, parenterally, via the pulmonary route, nasal, sublingually, lingually, buccally, rectally, vaginally, dermally, transdermally, conjuntivally, otically or as an implant or stent.
  • Suitable for oral administration forms which function according to the prior art and deliver the compounds of the invention rapidly and/or in a modified manner and which comprise the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example, with coatings which are resistant to gastric juice or dissolve with a delay or are insoluble and control the release of the compound of the invention), tablets which disintegrate rapidly in the oral cavity, or films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can take place with avoidance of an absorption step (for example intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with inclusion of absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation (inter alia, power inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films/wafers or capsules, to be administered lingually, sublingually or buccaly, suppositories, preparations for the eyes and the ears, eye baths, ocular insert, ear drops, ear powders, ear- rinses, ear tampons, vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia, power inhalers, nebulizers
  • nasal drops solutions, sprays
  • tablets, films/wafers or capsules to be administered lingually, sublingually or buccaly, suppositories, preparations
  • the compounds according to the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable excipients. These excipients include, inter alia, - -
  • fillers and excipients for example cellulose, microcrystalline cellulose, such as, for example, Avicel®, lactose, mannitol, starch, calcium phosphate such as, for example, Di-Cafos®),
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants, emulsifiers, dispersants or wetters for example sodium dodecyle sulphate, lecithin, phospholipids, fatty alcohols such as, for example, Lanette®, sorbitan fatty acid esters such as, for example, Span®, polyoxyethylene sorbitan fatty acid esters such as, for example, Tween®, polyoxyethylene fatty acid glycerides such as, for example, Cremophor®, polyox
  • buffers and also acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine),
  • binders for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids such as, for example, Carbopol®, alginates, gelatine
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®
  • modified starch carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate such as, for example, Explotab®, cross- linked polyvinylpyrrolidon, croscarmellose-sodium such as, for example, AcDiSol®
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas such as, for example, Aerosil®
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®), capsule materials (for example gelatine, hydroxypropylmethylcellulose), - -
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as, for example, Eudragit®, polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates such as, for example, Eudragit®, polyvinylpyrrolidones such as, for example, Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers
  • plasticizers for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gall ate
  • antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gall ate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the present invention furthermore relates to medicaments or a pharmaceutical composition comprising at least one compound according to the invention, conventionally together with one or more inert, nontoxic, pharmaceutically suitable excipient, and their use for the purposes mentioned above.
  • the compounds of the invention of general formula (I) and/or the pharmaceutical composition of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • the pharmaceutical composition can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day.
  • a single dose unit of the pharmaceutical composition can contain, e.g., from about 0.01 mg to about 4000 mg, preferably about 0.1 mg to about 2000 mg, more preferably about 0.5 to about 1500 mg, most preferably about 1 to about 500 mg, of the active compound.
  • Solvent ratios, dilution ratios and concentration data of liquid/liquid-solutions refer in each case to the volume.
  • the compounds of the present invention can be used alone or, if required, in combination with one or more further pharmacologically active substances, provided that this combination does not lead to undesirable and unacceptable side effects.
  • the present invention therefore further provides medicaments and compositions comprising an inventive compound and one or more further active ingredients, especially for prophylaxis and/or treatment of the aforementioned disorders.
  • the compounds of formula (I) can be combined with known antihyperproliferative, cytostatic or cytotoxic chemical and biological substances for treatment of cancer.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the - 7 -
  • non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • (chemotherapeutic) anti-cancer agents includes but is not limited to
  • alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®),
  • Thiotepa (Thiotepa Lederle®), Melphalan (Alkeran®), or chloroethylnitrosourea (BCNU);
  • platinum derivatives like cisplatin platinum derivatives like cisplatin (Platinex® BMS), oxaliplatin (Eloxatin®), satraplatin or carboplatin (Cabroplat® BMS);
  • antimitotic agents / tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine,
  • Taxanes such as Paclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as well as new formulations and conjugates thereof (like the nanoparticle formulation Abraxane® with paclitaxel bound to albumin), epothilones such as Epothilone B
  • topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin / Adriblastin®), epipodophyllotoxins (examplified by Etoposide / Etopophos®) and camptothecin and camptothecin analogs (exemplified by Irinotecan / Camptosar® or Topotecan /
  • pyrimidine antagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®),
  • purine antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanine or fludarabine (Fludara®) and
  • folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®).
  • folic acid antagonists such as methotrexate (Farmitrexat®) or premetrexed (Alimta®).
  • target specific anti-cancer agent includes but is not limited to
  • kinase inhibitors such as e.g. Imatinib (Glivec®), ZD-1839 / Gefitinib (Iressa®), Bay43-9006 (Sorafenib, Nexavar®), SU11248 / Sunitinib (Sutent®), OSI-774 / Erlotinib (Tarceva®), Dasatinib (Sprycel®), Lapatinib (Tykerb®), or, see also below, Vatalanib, Vandetanib (Zactima®) or Pazopanib;
  • proteasome inhibitors such as PS-341 / Bortezomib (Velcade®);
  • histone deacetylase inhibitors like SAHA (Zolinza®), PXD101, MS275, MGCD0103,
  • heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG) or 17- - -
  • VTAs vascular targeting agents
  • combretastin A4 phosphate or AVE8062 / AC7700 anti-angiogenic drugs like the VEGF antibodies
  • anti-angiogenic drugs like the VEGF antibodies, such as Bevacizumab (Avastin®), or KDR tyrosine kinase inhibitors such as PTK787 (Vatalanib®) or Vandetanib (Zactima®) or Pazopanib;
  • Rituxan® Alemtuzumab (Campath®), Tositumomab (Bexxar®), C225/ Cetuximab (Erbitux®), Avastin (see above) or Panitumumab (Vectibix®) as well as mutants and conjugates of monoclonal antibodies, e.g., Gemtuzumab ozogamicin (Mylotarg®) or Ibritumomab tiuxetan (Zevalin®), and antibody fragments;
  • oligonucleotide based therapeutics like G-3139 / Oblimersen (Genasense®) or the DNMT1 inhibitor MG98;
  • TLR 7/8 agonists like Resiquimod as well as immunostimulatory RNA such as TLR 7/8 agonists;
  • hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen or Raloxifen), an ti- androgens
  • LHRH analogs e.g. Leuprolide, Goserelin or Triptorelin
  • aromatase inhibitors e.g. Femara, Arimedex or Aromasin
  • target specific anti-cancer agents include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as 5-Aza-2'-deoxycytidine (Decitabine, Dacogen®) and 5-azacytidine (Vidaza®), alanosine, cytokines such as interleukin-2, interferons such as interferon a2 or interferon- ⁇ , bcl2 antagonists (e.g. ABT-737 or analogs), death receptor agonists, such as TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists (e.g. TRAIL receptor agonists like mapatumumab or lexatumumab).
  • ATRA all-trans retinoic acid
  • DNA methyltransferase inhibitors such as 5-Aza-2'-deoxycytidine (Decitabine, Dacogen®) and 5-azacytidine (Vid
  • anti-cancer agents include, but are not limited to, 1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene,
  • cetuximab chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizum
  • the compounds of formula (I) can be combined with antibodies, for example aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tositumumab or trastuzumab, and also with recombinant proteins.
  • antibodies for example aflibercept, alemtuzumab, bevacizumab, brentuximumab, catumaxomab, cetuximab, denosumab, edrecolomab, gemtuzumab, ibritumomab, ipilimumab, ofatumumab, panitumuma
  • the compounds of formula (I) can be used in combination with treatments directed against angiogenesis, for example axitinib, bevacizumab, cediranib, copanlisib, lenalidomide, pomalidomide, regorafenib, sorafenib, sunitinib, or thalidomide.
  • treatments directed against angiogenesis for example axitinib, bevacizumab, cediranib, copanlisib, lenalidomide, pomalidomide, regorafenib, sorafenib, sunitinib, or thalidomide.
  • treatments directed against angiogenesis for example axitinib, bevacizumab, cediranib, copanlisib, lenalidomide, pomalidomide, regorafenib, sorafenib, sunitinib, or thalidomide.
  • the compounds of the invention can also be used in conjunction with radiotherapy and/or surgical intervention.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallisation. In some cases, impurities may be stirred out using a suitable solvent.
  • the compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g., Biotage®SNAP cartridges containing stationary phases such as silica gel (KP-Sil cartridges), NH-functionalised media (KP-NH cartridges) or reversed phase CI 8 spherical silica (KP-C18-HS cartridges), in combination with a suitable chromatographic system such as an Isolera system (Biotage) and eluents such as, for example, gradients of hexane/ethyl acetate or DCM/methanol.
  • a suitable chromatographic system such as an Isolera system (Biotage) and eluents
  • silica gel has been used herein as stationary phase in flash chromatography.
  • the compounds may be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the IUPAC names of the examples and intermediates were generated using the program 'ACD/Name batch version 12.01 ' from ACD LABS, and were adapted if needed.
  • reaction mixture was stirred under air at room temperature over night, cooled down to 0°C and treated with water (50 ml) and 4M aqeous hydrochloride solution (50 ml). The mixture was stirred at room temperature for 30 min followed by the addition of 4M aqeous hydrochloride solution until pH 4. The suspension was filtrated, the filter cake was washed with water, isopropanol and hexane and dried in vacuo to give 4.85 g (34% of theory) of the title compound.
  • Diethylaminosulfur trifluoride 60.0 mL (454 mmol, was added to a solution of ethyl 3-methyl-2- oxobutanoate, 23.0 g, (160 mmol), in dichloromethane, 500 mL, drop-wise at 0 °C over an hour. The mixture was warmed to room temperature and stirred for 18 hours then added to saturated aqueous sodium hydrogen carbonate, 300 mL. The mixture was separated, and the aqueous layer was extracted with dichloromethane. The combined organic portions were washed with water, brine and dried over sodium sulfate, filtered and concentrated below 40 °C, above 600 mbar.
  • en-4-one (intermediate 15A) (55% purity), 2.00 g (6.17 mmol), in ethanol, 7.0 mL, and the mixture was stirred at 80 °C for 18 hours, then 90 °C for 24 hours. The mixture was then concentrated, diluted with ethyl acetate and added to water. The mixture was extracted with ethyl acetate once and dichloromethane three times, and the organic portions washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Methyl 3-amino-2-methylbenzoate (1.0 g, 6.05 mmol) was solved in toluene (7.5 ml).
  • Ethyl 3- oxobutanoate (0.87 g, 6.66 mmol) and 4-methylbenzenesulfonic acid monohydrate (10 mg, 52.6 ⁇ ) were added and the reaction mixture was stirred under reflux (Dean-Stark).
  • Ethyl 3- oxobutanoate (0.87 g, 6.66 mmol) and 4-methylbenzenesulfonic acid monohydrate (10 mg, 52.6 ⁇ ) were added and the reaction mixture was stirred at room temperature over 48 h and then refluxed for 7 h. The reaction mixture was concentrated in vacuo.
  • Methyl 4-chloro-2,8-dimethylquinoline-7-carboxylate (intermediate 21A) (2.1 g, 8.4 mmol) was suspended in methanol (10 ml) and treated with 2M aqeous sodium hydroxide solution. The reaction mixture was stirred for 2 h at room temperature and 4 h at 70°C. The reaction mixture was diluted with water, filtrated and brought to pH7 by addition of 2M aqeous hydrochloride solution. The mixture was extracted with butanol. The organic phase was filtrated via hydrophobic filter MN 617 WA (Macherey-Nagel) and concentrated in vacuo to give 2.25 g (91% of theory) of the title compound.
  • Methyl 4-hydroxy-2,8-dimethylquinoline-7-carboxylate (1.15 g, 4.96 mmol) was suspended in tetrahydrofurane (10 ml) and treated with 2M aqeous sodium hydroxide solution (3.7 ml). The reaction mixture was stirred over night at room temperature. Then, further 2M aqeous sodium hydroxide solution (2.5 ml) was added and the mixture was stirred at room temperature for another night. The reaction mixture was diluted with ethylacteate, isopropanole and saturated aqeous ammonium chloride solution. The phases were separated and the organic phase was washed - -
  • Example 13 4- ⁇ 4-r(Dimethvlamino)methvl1phenyl j-2,8-dimethvl-N-r(6-methyl-2-oxo-4-propvl- l,2-dihydropyridin-3-yl)methyl]quinoline-7-carboxamide - -
  • EZH2 wild type (wt) inhibitory activities of the compounds described in the present invention were quantified using a scintillation proximity assay (SPA) which measures methylation by the enzyme of the synthetic, biotinylated peptide ARTKQTAR-[Kme3]-
  • SPA scintillation proximity assay
  • EZH2wt in aqueous assay buffer [50 mM Hepes pH 7.5 (Applichem), 2.75 mM dithiothreitol (DTT, Sigma), 0.01 % (w/v) bovine serum albumin (BSA, Sigma), 0.01 % (v/v) Pluronic (Sigma)] were added to the compounds in the test plate to a final enzyme concentration of typically ⁇ 0.7-1.0 ng/ ⁇ (this parameter was adjusted depending on the activity of the enzyme lot in order to be within the linear dynamic range of the assay).
  • reaction was stopped by adding 3 ⁇ of Streptavidin PS SPA imaging beads (Perkin Elmer, final concentration of 1.562 ⁇ g/ ⁇ l) and "cold" SAM (AK Scientific, 250 ⁇ final concentration) for non-specific binding reduction. Plates containing the stopped reaction were sealed with transparent adhesive foil (Perkin Elmer), centrifuged (2 min., 1500 rpm), and further incubated overnight at 4°C in order to allow the SPA signals to develop.
  • Streptavidin PS SPA imaging beads Perkin Elmer, final concentration of 1.562 ⁇ g/ ⁇ l
  • SAM AK Scientific, 250 ⁇ final concentration
  • the amount of product was evaluated by measuring the energy transfer from the ⁇ -particles emitted by the 3H-labeled substrate to the Europium scintillator co-polymerized in the polystyrene matrix of the PS imaging beads, using the standard settings for this purpose of a Viewlux (Perkin-Elmer) CCD plate imaging device (emission filter 613/55 (IFP). The resulting scintillation counts were taken as indicator for the amount of methylated peptide per well.
  • a Viewlux (Perkin-Elmer) CCD plate imaging device emission filter 613/55 (IFP).
  • IC50 values were calculated by fitting the normalized inhibition data to a 4-parameter logistic equation using either a Bayer-proprietary tool or the "Screener" analysis software from Genedata.
  • EZH2 Y641N inhibitory activities of the compounds described in the present invention were quantified using a scintillation proximity assay (SPA) which measures methylation by the enzyme of the synthetic, biotinylated peptide ARTKQTARKSTGGKAPRKQLATKAAR-K(Me2)- - -
  • SPA scintillation proximity assay
  • SAPATGGVKKPHR-K(Btn)-Amid x TFA Biosyntan
  • H3(l-40)me2K27 The human mutant PRC2- EZH2 Y641N multiprotein complex used in the assay (composed by full length recombinant proteins His-EZH Y641N, His-SUZ12, His-AEBP2, Flag-EED and His-RbAp48) was either purchased from BPS Bioscience or produced in-house by co-expression in Sf9 insect cells with N-terminal 6xHis or FLAG-tags and purification by affinity chromatography on an Anti-FLAG M2 (Sigma) column followed by a desalting step on a DS 26/10 column (GE Healthcare).
  • EZH2 Y641N in aqueous assay buffer [50 mM Hepes pH 7.5 (Applichem), 2.75 mM dithiothreitol (DTT, Sigma), 0.01 % (w/v) bovine serum albumin (BSA, Sigma), 0.01 % (v/v) Pluronic (Sigma)] were added to the compounds in the test plate to a final enzyme concentration of typically ⁇ 0.95 ng/ ⁇ (this parameter was adjusted depending on the activity of the enzyme lot in order to be within the linear dynamic range of the assay).
  • reaction was stopped by adding 3 ⁇ of streptavidin PS SPA imaging beads (Perkin Elmer, final concentration of 1.562 ⁇ g/ ⁇ l) and "cold" SAM (AK Scientific, 250 ⁇ final concentration) for non-specific binding reduction. Plates containing the stopped reaction were sealed with transparent adhesive foil (Perkin Elmer), centrifuged (2 min., 1500 rpm), and further incubated overnight at 4°C in order to allow the SPA signals to develop.
  • streptavidin PS SPA imaging beads Perkin Elmer, final concentration of 1.562 ⁇ g/ ⁇ l
  • SAM AK Scientific, 250 ⁇ final concentration
  • the amount of product was evaluated by measuring the energy transfer from the ⁇ -particles emitted by the 3H-labeled substrate to the Europium scintillator co-polymerized in the polystyrene matrix of the PS imaging beads, using the standard settings for this purpose of a Viewlux (Perkin-Elmer) CCD plate imaging device (emission filter 613/55 (IFP). The resulting scintillation counts were taken as indicator for the amount of methylated peptide per well.
  • a Viewlux (Perkin-Elmer) CCD plate imaging device emission filter 613/55 (IFP).
  • IC5 0 values were calculated by fitting the normalized inhibition data to a 4-parameter logistic equation using either a Bayer-proprietary tool or the "Screener" analysis software from Genedata.
  • H3K27me3 Quantification of Histone H3 Lys27 Trimethylation (H3K27me3) after small molecule treatment of cancer cells
  • H3K27me3-assay based on High-Content Analysis (HCA) (Luense et al., J Biomol Screen. 2015 Feb; 20(2): 190-201) enables the biological characterization of compounds inhibiting histone methyl transferase EZH2.
  • HCA High-Content Analysis
  • Cultivated cells of the human triple negative basal-B breast adenocarcinoma tumor cell line MDA- MB-231 (ATCC HTB-26) were plated at a density of 2500 cells per well in a 384-well microtiter plate in 20 ⁇ RPMI 1640 supplemented with 1 % (v/v) glutamine, 1 % (v/v) penicillin, 1% (v/v) streptomycin and 10% (v/v) fetal calf serum.
  • test compounds solubilized in dimethyl sulfoxide (DMSO) were added at various concentrations (0 ⁇ , as well as in the range of 0.005 ⁇ - 30 ⁇ ; the final concentration of the solvent DMSO was 0.5% (v/v)).
  • DMSO dimethyl sulfoxide
  • Cells were incubated at 37°C for 72h in the presence of test compounds. Thereafter, cells were fixed with 4% (v/v) paraformaldehyde in phosphate buffered saline (PBS) at room temperature for 12min, permeabilized using 0.5% (v/v) Triton XTM 100 in PBS and blocked with 1 % (v/v) bovine serum albumin (BSA) in PBS.
  • PBS phosphate buffered saline
  • the cells were incubated with the histone-H3-specific H3K27me3 primary antibody (Cell Signaling #9733), followed by the species-specific fluorescent conjugated secondary antibody DyLightTM488-conjugated goat anti-mouse (Jackson Immuno Research #115-486-062) and Hoechst 33342 stain for chromatin staining and determination of total cell number.
  • Primary antibodies were diluted in 1% (v/v) BS A/PBS containing 0.5% (v/v) Triton XTM 100 in PBS and the cells were incubated at 4°C for 16h after one hour blocking with the antibody diluent.
  • Image acquisition for cells was carried out using the confocal imaging system OPERA® (PerkinElmer). Images were captured using two channels: Hoechst 33342 stain (DNA) and DyLightTM488 (H3K27me3 staining); and were analyzed using the MetaXpress® software (Molecular Devices). Exposure times were chosen for individual experiments to prevent saturation and allow for quantification in the linear range. A minimum of 1000 cells in 5 field views were analyzed per well using lOx water immersion objective with a two-fold binning.
  • the image analysis routine was developed in MetaXpress®.
  • the standardized image-analysis module "Count Nuclei" and the images of the DNA-channel were used for nuclei segmentation.
  • the segmented nuclei were filtered for size, shape and signal intensity to exclude possible apoptotic and non-viable cells along with metaphase nuclei. These phenotypes result in overestimated antibody signals, due to their strong chromatin compaction.
  • binary object masks were calculated from the segmented and positively selected nuclei.
  • the binary masks served as templates to be superimposed over the images of the H3K27me3 channel.
  • the nuclear H3K27me3 average signal intensity was quantified for every image set.
  • the assay raw data were further analyzed by four parameter logistic regression analysis using Genedata's Assay Analyzer and Condoseo software to determine the IC 50 value for each tested compound.
  • An empty field means "not determined yet”

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Abstract

Cette invention concerne des quinoléines de formule générale (I), leur procédé de préparation, des intermédiaires pour les préparer, des compositions pharmaceutiques comprenant au moins un desdits composés, et leur utilisation.
PCT/EP2016/068844 2015-08-12 2016-08-08 Inhibiteurs quinoléine d'ezh2 Ceased WO2017025493A1 (fr)

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Cited By (4)

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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
WO2020020374A1 (fr) * 2018-07-27 2020-01-30 苏州信诺维医药科技有限公司 Composé de benzène polysubstitué et son procédé de préparation et son utilisation
WO2024012461A1 (fr) * 2022-07-12 2024-01-18 上海赛岚生物科技有限公司 Inhibiteur de la méthyltransférase et son utilisation

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WO2012118812A2 (fr) * 2011-02-28 2012-09-07 Epizyme, Inc. Composés hétéroaryles bicycliques substitués condensés en 6,5
WO2013120104A2 (fr) * 2012-02-10 2013-08-15 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, leurs compositions et utilisations
WO2014151142A1 (fr) * 2013-03-15 2014-09-25 Constellation Pharmaceuticals, Inc. Modulateurs d'enzymes de modification du méthyle, compositions et utilisations associées

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WO2012118812A2 (fr) * 2011-02-28 2012-09-07 Epizyme, Inc. Composés hétéroaryles bicycliques substitués condensés en 6,5
WO2013120104A2 (fr) * 2012-02-10 2013-08-15 Constellation Pharmaceuticals Modulateurs d'enzymes de modification par méthylation, leurs compositions et utilisations
WO2014151142A1 (fr) * 2013-03-15 2014-09-25 Constellation Pharmaceuticals, Inc. Modulateurs d'enzymes de modification du méthyle, compositions et utilisations associées

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US12122833B2 (en) 2016-05-11 2024-10-22 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
WO2020020374A1 (fr) * 2018-07-27 2020-01-30 苏州信诺维医药科技有限公司 Composé de benzène polysubstitué et son procédé de préparation et son utilisation
CN113480525A (zh) * 2018-07-27 2021-10-08 苏州信诺维医药科技股份有限公司 多取代苯环化合物、制备方法及其用途
CN113480525B (zh) * 2018-07-27 2024-02-27 苏州信诺维医药科技股份有限公司 多取代苯环化合物、制备方法及其用途
US12390472B2 (en) 2018-07-27 2025-08-19 Evopoint Biosciences Co., Ltd. Polysubstituted benzene compound and preparation method and use thereof
WO2024012461A1 (fr) * 2022-07-12 2024-01-18 上海赛岚生物科技有限公司 Inhibiteur de la méthyltransférase et son utilisation

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